Abstract Background Neratinib, an oral irreversible pan-HER tyrosine kinase inhibitor, was approved in 2020 in China for the extended adjuvant treatment of HER2+ early breast cancer (EBC) adult patients. Diarrhea is the most common treatment-related adverse event associated with neratinib and an important factor impacting patients’ quality of life during therapy. Evaluating the effectiveness of anti-diarrheal prophylaxis measures and patient-reported outcomes in real-world settings is essential. Method NER-Tree is an ongoing, prospective, multi-center, non-interventional study (NCT05491057) that aims to enroll 500 patients with HER2+ early breast cancer (EBC) starting 1-year extended adjuvant neratinib. Diarrheal prophylaxis for neratinib was not required. Prespecified interim analyses are planned after the recruitment of 250 and 500 patients. Primary and secondary objectives are to characterize real-world treatment patterns and assess neratinib's safety profile including diarrhea, respectively. The exploratory objectives include patient-reported quality of life (QoL), and pattern of breast cancer recurrences. Here we report safety data in the second interim analysis, focusing on diarrhea management and patient-reported outcomes. Results As of 28 October 2024, 500 patients were included in the analysis. Diarrhea (86.4%), nausea (18.2%), fatigue (15.6%), and decreased appetite (14.4%) were the most common AEs of any grade. Serious adverse events (SAEs) were reported in 3.4% of the patients. Diarrhea was predominantly reported as Grade 1 or 2 (69.6%), while Grade 3 diarrhea was reported in 16.8% of the patients. No grade 4 diarrhea was observed. The median time from the initiation of neratinib treatment to the onset of diarrhea was 3.0 days (interquartile range IQR 2.0,6.0). Diarrhea was the most common adverse event leading to dose reduction (14.4% of cases vs. 18.2% for all adverse events combined), dose interruption (18.0% vs. 33.6%), and permanent discontinuation (4.2% vs. 6.8%). Patients who initiated neratinib at 240 mg experienced a lower incidence of Grade 3 diarrhea compared to those who started at 240 mg (12.2% vs. 26.1%). Anti-diarrheal strategies were adopted at least once in 297 patients (59.4%), including drug prophylaxis (loperamide or other agents; 18.0%), dose escalation (28.0%), or a combination of both strategies (13.4%). Compared to no prophylaxis (28.6%, 32/112), all strategies reduced the incidence of Grade ≥3 diarrhea: most substantially with the combination approach (9.0%, 6/67), followed by dose escalation (17.9%, 25/140) and drug prophylaxis (20.8%, 11/53).Neratinib initiation induced concomitant transient deteriorations in patient-reported outcomes, peaking at Day 30 across all instruments. The EQ-5D-5L showed maximal declines in Health Status (-4.5) and Utility Index (-0.0492), while FACIT instruments revealed greater disease-specific impacts: FACIT-F Trial Outcome Index (fatigue/function) decreased by 10.31 points, FACIT-G Total (general QoL) by 4.85, and FACIT-D Total (breast cancer-specific) by 11.58. All metrics demonstrated progressive recovery through Day 60 toward near-baseline levels by Day 180. Conclusion This study provides further insights on the pattern of diarrhea associated with neratinib and preventive anti-diarrheal measures. Dose escalation and drug prophylaxis combined strategy was the most effective approach in reducing the incidence of Grade 3 diarrhea associated with neratinib. Patient-reported outcomes showed an initial deterioration until Day 30 during neratinib treatment initiation, possibly related to the occurrence of treatment-emergent adverse events, followed by a functional/QoL recovery afterward. Citation Format: X. Wang, X. Liu, H. Liu, S. Ma, Y. Zhang, J. Gao, J. Ye, J. Ma, A. Zhang, Y. Wang, X. Wu, J. Wu, Y. Chen, S. Zhang, Q. Ouyang, G. Jiang, J. Liu, F. Tian, S. Yang, J. Zhang. Ner-tree study interim analysis of safety and patient-reported outcomes in patients with human epidermal growth factor receptor 2 positive (HER2+) early breast cancer (eBC) treated with neratinib in China abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-10-29.
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